6-fluoro-17 alpha-alkynyl-4-androstenes



' thereof,

Unite States 7 2,838,549 G-FLUORO-17wALKYNYL-A-ANDROSTENES No Drawing. Application February 19, 1958 Serial No. 716,030

21 Claims. (Cl. 260-39145) The present invention relates to new 6t;- and 6 3- fluorinated steroids and is more particularly concerned with certain 6-iluoro-ll-oxygenated-17 8-hydroxy-17alower alkynyl hydrocarbon-4-androsten-3-ones and the 17-a-cyl'ates thereof, for example, 6-fluoro-1l[3,17;3-dihy droxy 17a ethinyl 4 androsten 3 ones [6 fluoro- 1lfl-hydroxy-I7a-ethinyltestosterones] 6-fluoro-1 113,173- dihydroxy 17a ethinyl 19 nor 4 androsten 3- ones [6-fluoro-1 lp-hydroxy-17u-ethinyl-19-nortestosterones], 6 fluoro 17/3 hydroxy 17cc ethinyl- 4 androstene-3,1 l-diones [6,-fluoro-l 1-keto-17a-ethinyltestosterones], 6 fluoro-17fi hydroxy- 17a-ethinyl-19-nor-4-androstene 3,11 diones [6 fluoro 11 keto 17ozethinyl-l9-n0rtestosterones], the 17-acylates thereof and novel steroid intermediates and methods used in the preparation thereof.

The novel end product compounds of this invention are represented by the formula:

wherein R is methyl or hydrogen, R is hydrogen or a lower alkyl radical, R is hydrogen or an *acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic. acid, containing from one to twelve carbon atoms, inclusive, and X represents a carbonyl radical C=O) or a hydroXy-methylene radical CHOH). The term lower alkyl radical, as used herein, refers to an alkyl radical of from one to four carbon atoms, inclusive, e. g., methyl, ethyl, propyl, isopropyl, bntyl, isobutyl, and tertiary butyl.

It is an object of the instant invention to provide novel 6-fluoro-1 l-oxygenated-17B-hydroxy-17a-lower alkynyl hydrocarbon-4-androsten-3-ones and the 17-acylates for example, the 6-fluoro-1lfl-hydroxy-lhethinyltestosterones, 6-fluoro-1lB-hydroxy-17a-ethinyl-19- nortestosterones, 6 fluoro 11 keto 17oz ethinyltestosterones, 6-fluoro- 1 1-ket0-17a-ethinyl-19-nortestosterones and the l7-acylates thereof and novel intermediates and methods in the production thereof. Other objects of this invention will be apparent to those skilled in the art to Which this invention pertains.

The novel end products of this invention, the compounds of Formula I, possess useful therapeutic properties as orally and parenterally active progestational agents. They aflect the secretion of gonadotropins and thus regulate ovulation and endometrial and placental development and, particularly when used in conjunction with estrogens, e. g., ethinylestradiol and/ or androgens, e. g.,

atent O 2,333,549 Patented June 10, 1958 Halotestin (9a-fluoro-l 1 ii-hy'droxyl 7-inethyltestosterone), reduce fertility and constitute efiective therapy for dysrnenorrhea, amenorrhea, endornetriosis, threatened abortion and related gynocological disorders. Administration of these steroids can be in conventional dosage forms such as pills, tablets, capsules, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid hormones for injectable products. Microcrystalline aqueous suspensions or oil solutions can be prepared for parenteral dosage.

The novel steroids of Formulae Ia, lb, 10, and Id, can be prepared according to the following reaction sequence:

CH3 CH3 0 OH I ogen no no i 1 A II In Ra N O:

CH3 CH5 (|)H (IDAc --OECR1 c2012, oj HO 2 R Ic Ib wherein R and R have the sarne meaning as previously given, Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, and R is an alkylene group which, together with the nitrogen atom forms a ring containing from five to six members, inclusive, and which preferably contains less than nine carbon atoms.

One aspect of the process of the present invention comprises treating compounds of the type represented. by Formula H, for example, 6-fluoro-llB-hydroxy-S-(N- pyrrolidinyl)-3,5-androstadien-l7-one and 6-fluoro-1ltlhydroxy 3 (N pyrrolidinyl) 19 nor 3,5 an drostadien-17-one with potassium acetylide, prepared according to procedures known in the art, to obtain the compounds of Formula la, for example, 6-fiuoro-1 15,17,3- dihydroxy-17u-ethinyL4-androsten-3-ones and 6-fluoro- 11fl,l7;6- dihydroxy 17oz ethinyl 19 nor 4 androsten-3-ones. Other 3-enamines such as those prepared by treating 6-fluoro-11fl-hydroxyl-androstene-B,17- diones and 6 fluoro l1fi-hydroxy-l9-nor-4-androstenee 3,17-diones with other secondary amines and particularly secondary cyclic alkylene amines, for example, piperidine, C-alkyl substituted piperidines, e. g., 2,4-dimethylpyrrolidine, 3-isopropylpyrrolidine, 3,3-dimethylpyrroli dine, and the like, are suitable as starting materials.

Other alkali metal acetylides, for example, sodium or lithium acetylide can be substituted for potassium acetylide to add the side chain at the l7OC-pOSlllOI1.

The substitution of potassium methylacetylide (or other alkali metal methylacetylide) for potassium acetylide is productive of 6-fluoro-l 1B,l7fi-dihydroxy-l7ot-methylethinyl-4-androsten-3-ones and 6 fluoro 1lfi,l7,B-dihydroxy-17ot-methylethinyl-19-nor-4-androsten-3-ones. Similarly, the substitution of other potassium (or other alkali metal) alkyl-substituted acetylides, for example, potassium ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, and tertiary butylacetylide, for potassium acetylide is productive of 6 fluoro 11 5,17,8-dihydroxy-17a-ethylethinyl-4- androsten-3-ones, 6-fluoro-l1/3,l7fl-dihydroxy-l7a-propylethinyl-4-androsten-3-ones, 6 fluoro-115,1713-dihydroxyl7a-isopropylethinyl-4-androsten-3-ones, 6 fluoro 11B, l7fl-dihydroxy-l7a-butylethinyl-4-androsten 3 ones, 6- fluoro-l 1 8,17/3-dihydroxy-17a-isobutylethinyl-4-androsten- 3-ones, and 6-fluoro-l1,8,17 3-dihydroxy-Not-tertiary butylethinyl-4-androsten-3-ones, respectively, and their corresponding l9-nor compounds.

Following the reaction of the compounds of Formula II with an alkali metal acetylide (or an alkali metal alkylsubstituted acetylide), to add the side chain at the 17aposition, the reaction mixture is diluted with water, or an aqueous ammonium salt solution, for example, aqueous ammonium chloride solution and extracted with an inert organic solvent, for example, ether, and taken to a residue. The residue thus-obtained is then subjected to hydrolysis to effect removal of the 3-enamine group. The hydrolysis of the 3-enamine group is preferably carried out using a buffered solution, for example, a solution containing so- 4 dium acetate, water, acetic and methanol. The compounds of Formula Ia, for example, 6-fluoro-l1fi-hydroxy-l7a-ethinyltestosterones and 6-fluoro-llfi-hydroxyl7a-ethinyl-l9-nortestosterones are then recovered from the solution used to hydrolyze the 3-enamine group according to procedures well-known in the art, such as by extraction with water-immiscible solvents, e. g., methylene chloride, ether, benzene, or the like, followed by chromatography.

The 17-acylates represented by Formula lb, such as the l7-acylates of 6-fiuoro-l1,8-hydroxy-l7a-ethinyltestosterone and 6-fluoro-llfl-hydroxy-l7a-ethinyl-18-nortestosterone are obtained by allowing the compounds of Formula Ia to react with the anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containtaining from one to twelve carbon atoms, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid, e. g., cyclohexanecarboxylic, an alkaryl acid, e. g., benzoic, phenylacetic, 2-phenylpropionic, 0-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., succinic, adipic, a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, cinnamic, dibasic unsaturated acids (which can be converted into water-soluble, e. g., sodium, salts), e. g., maleic and citraconic.

Another aspect of the present invention comprises treating the compounds of Formula Ia, as as 6-fluorol1/3,17B-dihydroxy-17a-ethinyl-4-androsten-3-one and 6- fluoro-l 1,8, 17/3-dihydroxyl 7a-ethinyll9-nor-4-androsten- 3-one with an oxidizing agent, for example, chromic acid, potassium dichromate or SOdlllDl dichromate to obtain the compounds of Formula Ic, such as 6-fluoro-17/3-hydroxyl7a-ethinyl-4-androstene-3,ll-dione and 6-fluoro-l7fi-hydroxy-l7a-ethinyl-19-nor-4-androstene-3 ,1 l-dione, respectively. The oxidation can be carried out by a variety of methods, such as, for example, by oxidizing the compounds of Formula la in acetic acid solution with chromic anhydride, or sodium dichromate, or by oxidizing with chromic anhydride in the presence of pyridine. At the conclusion of the desired oxidation reaction, the excess chromic acid is generally destroyed by the addition of methyl alcohol, ethyl alcohol, and the like. Thereafter, the resulting ll-keto compounds of Formula Ic are recovered by conventional means, such as by crystallization, extraction with water-immiscible solvents, e. g., methylene chloride, ether, benzene, toluene, or the like, or by chromatography.

The l7-acylates represented by Formula Id, for example, the 17-acylates of 6-fluoro-l1-keto-17u-ethinyltestosterone and 6 fluoro 11 keto-l7a-ethinyl-l9-nortestosterone are obtained by allowing the compounds of Formula 10 to react with the anhydride of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, for example, a saturated straight-chain aliphatic acid, e. g., acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, a cycloaliphatic saturated acid, e. g., cyclohexane-carboxylic, an alkaryl acid, e. g., benzoic, phenylacetic, 2-phenylpropionic, o-, m-, and p-toluic, a saturated dibasic acid (which can be converted into watersoluble, e. g., sodium, salts), e. g., succinic, adipic, a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, cinnamic, dibasic unsaturated acids (which can be converted into water-soluble, e. g., sodium, salts), e. g., maleic and citraconic.

The starting materials, the compounds of Formula II, are prepared according to the procedures disclosed in Preparations l and 2 below.

The following preparations and examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1 A. 6/3-flu0r0-5a,1Ifl-dihydroxyandr0stane-3,II-dione Three grams of 5a,6or-epoxy-l1B-hydroxyandrostane-3, l7-dione 3,17-bis-(ethy1ene ketal), prepared according to the procedure disclosed in copending application Serial No. 661,626, filed May 27, 1957, in 25 milliliters of methylene chloride contained in a polyethylene bottle is treated with nine milliters of 48 percent hydrofluoric acid. The reaction mixture thus-obtained is stirred at room temperature for several hours and then cautiously poured into a mixture of 45 milliliters of methylene chloride and fifty milliliters of ice cold 1.5 molar aqueous sodium carbonate solution and stirred with caution. The mixture is exhaustively extracted with methylene chloride and the methylene chloride layer is washed with water and dried over sodium sulfate. Evaporation of the methylene chloride gives a residue containing 6B-fluoro-5a,ll;8-dihydroxyandrostane-3,l7-dione.

The residue containing 6,8-fluoro-5m,llfl-dihydroxyandrostane-3,l7-dione produced in Preparation 1A, is dissolved in 200 milliliters of chloroform and seven milliliters of ethyl alcohol and treated with anhydrous hydrogen chloride gas, whilst maintaining the temperature at approximately from minus five to minus ten degrees centigrade. The solution thus-obtained is washed with successive portions of water, aqueous sodium bicarbonate solution and water, dried over sodium sulfate, concentrated to 35 milliliters and chromatographed over 75 grams of activated alumina. The chromatographic column is eluted with Skellysolve B hexanes plus increasing proportions of acetone from two to fifty percent and collected in fiftymilliliter fractions. Fractions 8 through 19 are combined and the solvent removed by evaporation leaving a residue. The residue is recrystallized from methylene chloridedione, a crystalline solid.

C. 6-fluor0-1Ifl-hydroxyd-(N-pyrrolidinyl) -3,5-

androstadien-I Zone A mixture of 2.5 grams of 6u-fiuoro-l1/3-hydroxy-4 'ahdrostene-3,17-dione intwenty milliliters of methanol is heated to near the boiling point, cooled slightly and treated with 1.3 milliliters of pyrrolidine. The flask is scratched with a glass rod to induce crystallization. The reaction mixture is allowed to cool to room temperature and is then refrigerated at approximately zero degrees centrigrade for one hour. The precipitate of 6-fiuoro-1lfl-hydroxy-S-(N- pyrrolidinyl) 3,5 androstadien 17 one thus obtained is collected by filtration, washed with methanol and dried.

In the same manner as shown above, treating 6/3-fluoro- 115-hydroxy-4-androstene-3,l7-dione with pyrrolidine is productive of 6-fluoro-11B-hydroxy-3-(N-pyrrolidinyl)- 3,5-androstadien-17-one.

PREPARATION 2 A mixture of five grams of 19-nor-4-androstene-3,11,17- trione (U. S. Patent 2,757,186), 250 milliliters of benzene, twenty milliliters of ethylene glycol and 150 milligrams of p-toluenesulfonic acid is vigorously stirred and heated to reflux under a water trap until the reaction is complete. The reaction mixture is cooled, washed with five percent aqueous sodium carbonate solution and water and dried over sodium sulfate. crude residue of l9-n0r-5-androstene-3,11,17-trione 3,17- bis-(ethylene ketal).

The total crude residue obtained in Preparation 2A, is dissolved in fifty milliliters of tetrahydrofuran and added with stirring over approximately a five-minute period, under nitrogen, to a mixtureof two grams of lithium aluminum hydride and 100 milliliters of anhydrous ether. The mixture is stirred whilst ice cooling, followed by careful treatment of the mixture with twenty milliliters of water. The mixture is then diluted with 200 milliliters of ether, stirred and filtered to remove inorganic solids. The filtrate is washed with three fifty-milliliter portions of water, dried over sodium sulfate, and the mixture taken to dryness. The residue is recrystallized from ether to give llfi-hydroxy 19 nor 5 androstene 3,17 dione 3,17-bis-(ethylene ketal), a crystalline solid.

C. 5 (1,6(1-8I7OXY-1 l fi hydrxy-1 9-n0randr0stane-3J 7- dione 3,17-bis-(ethylene ketal) A mixture of two grams of 1lfi-hydroxy-19-nor-5-androstene-3,17-dione 3,17-bis-(ethylene ketal), forty milliliters of chloroform and 0.4 gram of sodium acetateiscoo-led in an ice-water bath and treated with four milliliters of forty percent peracetic acid. The cooled mixture is stirred vigorously for about two hours. The-cold bath is then removed and the mixture is stirred with forty milliliters of saturated aqueous sodium bicarbonate solution for approximatley one hour and exhaustively excrystalline solid.

A mixture of 1.7 grams of u,6ca-epoxy-1lB-hydroxy- 19 norandrostane 3,17 dione 3,17 bis (ethylene ketal) and sixteen milliliters of methylene chloridein a polyethylene bottle is treated with six milliliters of 48 Evaporation of the solvent gives a percent hydrogen fluoride and stirred vigorously at room temperature for several hours. The reaction mixture is carefully treated with a solution of ten grams of sodium bicarbonate in 125 milliliters of water and extracted with methylene chloride. The extract is washed'with water, dried over sodium sulfate, and the solvent removed by distillation. The residue, which contains 6p-fiuoro-5a,11fldihydroxy 19 norandrostane 3,17 dione is dissolved in methylene chloride and chromatographed over fifty grams of Florisil (synthetic magnesium silicate), followed by elution of the column using forty-milliliter fractions of SkellysolveB hexanes plus increasing proportions of acetone from one to fifty percent. The desired 6p-fiuoro- 50:,115 dihydroxy 19 norandrostane 3,17 dione is eluted first and the solvent is removed by evaporation.

E. 6 a-flltoro-l 1 j8-lzydroxy-1 9-n0r-4-androstene- 3,17-dione One gram of 6p fluoro 50:,115 dihydroxy 19 norandrostane-3,17-dione, eighty milliliters of chloroform and one milliliter of ethanol is cooled to approximately minus ten degrees centigrade and dry hydrogen chloride is passed through the mixture for several hours while allowing the temperature of the solution to warm to approximately zero degrees centigrade. The thus-obtained solution is diluted with milliliters of chloroform, washed with successive portions of water, aqueous sodium bicarbonate solution, and water and dried over sodium sulfate. The solvent is removed by distillation and the residue crystallized from acetone-Skellysolve B hexanes to give 60:- fluoro 11/8 hydroxy 19 nor 4 androstene 3,17- dione, a crystalline solid.

In the same manner shown in Preparation 1C, treating 6a fluoro 11,6 hydroxy 19 nor 4 androstene- 3,17 dione or 6,8 fluoro 11 3 hydroxy 19 -'nor 4- androstene 3,17 dione with pyrrolidine is productive of 6 fluoro 11,6 hydroxy 3 (N pyrrolidinyl) 19- nor-3,5-androstadiene-17-one.

To about fifty milliliters of liquid ammonia in a vessel equipped with a Dry Ice-acetone condenser there is added two grams of potassium. The potassium is added in' 9.25 gram to 0.5 gram portions, each portion being cut into small pieces. Following the addition of each portion of potassium, acetylene is bubbled into the solution until the reaction mixture is kept cold for several hours by.

means of the Dry Ice-acetone condenser, after which the reaction mixture is stirred for approximately eighteen hours and then allowed to come to room temperature. The reaction mixture is then diluted with fifty milliliters of ammonium chloride solution and extracted with ether. The extract is washed with water, dried over sodium sulfate and the solvent removed under reduced pressure. The residuethus-lobtained is heated at reflux for several hours in a buffered solution of six grams of sodium acetate, six milliliters of water, four milliliters of acetic acid and forty milliliters of methanol. The mixture thus-obtained is extracted with ether and the extract is washed with successive portions of water, dilute aqueous sodium carbonate solution and water and dried over sodium sulfate. The ether is removed by evaporation and the residue thus-obtained is dissolved in methylene chloride and chromatographed over fifty grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted with Skellysolve B hexanes plus increasing propor tions of acetone from one to 35 percent. Those fractions which show no infrared absorption bands in the C carbonyl region are combined and recrystallized from acetone-hexane to yield 6a-fiuoro-115,175-dihydroxy-17aethinyl-4-androsten-3-one. 65-fluoro-115,175-dihydroxy- 17ot-ethinyl-4-androsten-3-one is present in the crystallization mother liquors, and can be isolated by additional chromatography followed by crystallization from acetonehexane mixture.

In the same manner shown in Example 1A treating 6- fluoro-115-hydroxy-3-(N-pyrrolidinyl)-3,5 androstadien- 17-one with potassium methylacetylide and hydrolyzing the product in a buffered mixture is productive of 6- fiuoro-l 15-hydroxy-170-methylethiny1testosterone. Similarly, substituting other postassium alkyl-substituted acetylides, for example, potassium ethyl-, propyl-, isopropyl-, butyl-, isobutyland tertiary butylacetylide, for the potassium acetylide above, is productive of the corresponding 6-fluoro-1 15-l1ydroxy- 170t-alkylethinyltestosterone.

A solution containing one gram of 6a-fluoro-115,175- dihydroxy-17a-ethinyl-4-androsten-3-one in nine milliliters of propionic anhydride is heated under reflux until the reaction is substantially complete, usually for several hours. The propionic anhydride is then removed by evaporation and the residue is crystallized from aqueous methanol to give 6a-fluoro-115,175-dihydroxy-Not-ethinyl- 4-androsten-3-one 17-propionate. Treating 65-fluoro-115, 175-dihydroxy-17a-ethinyl-4-androsten-3-one with propionic anhydride as above is productive of 65-fluoro-115, 175-dihydroxy-17oc-ethinyl-4-androsten-3-one 17-propionate.

In the same manner shown above, 6-fluoro-115,175- dihydroxy-17oc-ethinyl-4-androsten-3-one 17-cyclopentylpropionate, 6-fiuoro-115,l75-dihydroxy-17u-ethinyl-4-androsten-3-one 17-acetate, 6 fluoro-115,175-dihydroxy-17aethinyl-4-androsten-3-one l7-butyrate, 6-fluoro-1l5,l75- dihydroxy-17ot-ethinyl-4-androsten-3-one l7 -valerate, 6- fluoro1 15,175-dihydroxy-17a-ethinyl-4-androsten-3 one l7-hexanoate, 6-fluoro- 1 15,175dihydroxy-17a-ethinyl-4- androsten-3-one 17-laurate, 6-flu'oro-115,175-dihydroxy- 17ot-ethinyl-4-androsten-3-one l7-trimethylacetate, 6-fiuoro-l l 5, l75-dihydroxy-17a-ethinyl-4-androsten-3-one 17- isobutyrate, 6-fiuoro-l 15,175-dihydroxy-17a-ethinyl-4androsten-3-one 17-isovalerate, 6-fluoro-l15,175-dihydroxy- 17a-ethinyl-4-androsten-3--one 17-cyclohexanecarboxylate, 6-fluorol15,175-dihydroxy-17ot-ethinyl-4-androsten-3-one 17-benzoate, 6-fluoro-115,l75-dihydroxy-17a-ethinyl-4- androsten-3-one l7-phenylacetate, 6-fluoro-1l5,175-dihydroxy-17a-ethinyl-4-androsten-3-one 17- 5-phenylpropionate), 6-fluoro-l l5,175-dihydroxy-17a-ethinyl-4- androsten-3-one 17-(o-, m-, p-toluate), 6-fluoro-115,175-dihydroxy-17a-ethinyl 4-androsten-3-one l7-hemisuccinate, 6- fluoro-115,175-dihydroxy-l7a-ethinyl-4-androsten-3 one 17-herniadipate, 6-fiuoro-1 15,175-dihydroxy-Hot-ethinyl- 4-androsten-3-one 17-acrylate, 6-f1uoro-l15,175-dihydroxy-17a-ethinyl-4-androsten-3-one 17-crotonate, 6-fluoro-l l5,175-dihydroxy-17ot-ethinyl-4-androsten-3-0ne 17- undecylenate, 6-fluoro-115,175-dihydroxy-l7a-ethinyl-4- androsten-3-one 17-propiolate, 6-fluoro-115,175-dihydroxy-17a-ethinyl-4-androsten-3-one 17-cinnamate, 6- fluoro-115,175-dihydroxy-17a-ethinyl-4-androsten-3 one 17-maleate, and 6-fluoro-115,175-dihydroxy-17a-ethinyl- 4-androsten-3-one 17-citraconate are prepared by dissolving 6-fluoro-l 15,175-dihydroxy-l7a-ethinyl-4-androsten-3- one in the appropriate acid anhydride and heating, for

example, at between and degrees centigrade. The crude ester is isolated in accordance with the procedure above and recrystallized to give the 6-fluoro-115,175-dihydroxy-l7wethinyl-4-androsten-3-one 17-acylate. If the corresponding acid anhydride is solid, an inert solvent such as toluene, xylene, or dioxane can be added to effect solution and to provide a liquid esterification reaction medium.

The 17-propionates of 6-fluoro-115,175-dihydroxy- 17oz methylethinyl 4 androsten 3 one, 6 fluoro- 115,l75 dihydroxy 17a ethylethinyl 4 androsten 3-one, 6 fluoro 115,175 dihydroxy 17oz propylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17oz isopropylethiny-l 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17a butylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17a isobutylethinyl 4 androsten 3 one, and 6- fluoro 115,175 dihydroxy 17a tertiary butylethinyl- 4-androsten-3-one are obtained in the same manner as in Example 1B by treating the corresponding steroid with propionic anhydride. Other 17-acylates of 6-fiuor0- 115,175 dihydroxy 17a methylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy-17u-ethylethinyl 4 androsten 3 one, 6 fluoro 115,175 di- H hydroxy 17m propylethinyl 4- androsten 3 one, 6-

fluoro 115,175 dihydroxy 171x isopropylethiny-l 4- androsten 3 -one, 6 fluoro 115,175 dihydroxy cbutylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17o: isobutylethinyl 4 androsten 3 one, and 6 fluoro 115,175 dihydroxy 171x tertiary butylethinyl-4-androsten-3-one are produced in the same mannet as in Example 113 by dissolving 6-fluoro-115,175-di- 'hydroxy 17m methylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17a ethylethinyl 4- andr-osten 3 one, 6 fluoro 115,175 dihydroxy- 170: propylethinyl 4 androsten 3 one, 6 fluoro- 1l5,175 dihydroxy 17a isopropylethinyl 4 androsten 3 one, 6-fiuoro 115,175 dihydroxy 17a butylethinyl 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17cc isobutylethinyl 4 androsten 3 one or 6 fluoro 115,175 dihydroxy 17a tertiary butylethinyl-4-androsten-3-one, in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated and crystallized in accordance with the procedure of Example 1B.

EXAMPLE 2 A. 6-flu0ro-115,1 7 5-dihydroxy-1 7u-ethinyl- 19-n0r-4-androsten-3-0ne In the same manner as shown in Example 1A, treating 6 fluoro 115 hydroxy 3 (N pyrrolidinyl)- l9-nor-3,5-androstadien-3-one with potassium acetylide, treating the reaction mixture with aqueous ammonium chloride and hydrolyzing the resulting enamine with a mixture of sodium acetate, acetic acid, water and methanol is productive of 6ot-fiuoro-115,175-dihydroxy-lhethinyl l9 nor 4 androsten 3 one and 65 fluoro- 115,175 dihydroxy 17cc ethinyl 19 nor 4 -androsten-3-one. Substituting potassium methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, or tertiary butylacetylide for potassium acetylide in the above process is productive of the corresponding 6-fluoro-1l5,175-dihydroxy-l7amethylethinyl 19 nor 4 androsten 3 one, 6-fiuoro- 115,175 dihydroxy 17a. ethylethinyl 19 nor 4- androsten 3 one, 6 fluoro 115,175 dihydroxy- 170; propylethinyl 19 nor 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 17a isopropylethinyl- 1'9 nor 4 androsten 3 one, 6-fiuoro-115,175-dihydroxy 17a butylethinyl 19 nor 4 androsten-3- one, 6 fluoro 115,175 dihydroxy 17oz isobutylethinyl 19 nor 4 androsten 3 one, and 6 fluoro- 115,175 dihydroxy 17a tertiary butylethinyl 19-nor- 4-androsten-3-one.

In the same manner shown in Example 1B, treating 6- fluo'ro 115,175 dihydroxy 17a ethinyl 19 nor- 4 androsten 3 one with propionic anhydride is productive of 6 fluoro 115,175 dihydroxy 17a ethinyl- 19 nor 4 androsten 3 one l7-propionate.

In a like manner other 17-acylates are prepared by dissolving 6 fluoro 115,175 dihydroxy l7a-ethinyl 19 nor 4 androsten 3 one in the appropriate acid anhydride, heating, for example, at between 100 and 150 degrees centigrade and isolating the product as shown in Example 1 B.,

.The l7-propionates of 6-fluoro-115,175-dihydroxy-17amethylethinyl 19 nor 4 androsten 3-0ne, 6-fluoro- 115,175 dihydroxy 17a ethylethinyl 19 nor 4- androsten 3 one, 6-fluoro 115,175 dihydroxy 17apropylethinyl 19 nor 4 androsten 3 one, 6-fluoro- 115,175 dihydroxy 17oz isopropyl ethinyl 19 nor- 4 androsten 3 one, 6 fluoro 115,175 dihydroxy- 17oz butylethinyl 19 nor 4 androsten 3 one, 6- fiuoro 115,175 dihydroxy 17a isobutylethinyl 19- nor 4 androsten 3 one, and 6-fiuoro-115,175-dihydroxy 17a tertiary butylethinyl 19 nor 4 androsten-3-one areobtained in the same manner as in ExampleilB by treating the corresponding steroid with propionic anhydride. Other 17-acylates of 6-fiuoro-115,175-d1- hydroxy 17a methylethinyl 19 nor 4 androsten- 3 one, 6 fluoro 115,175 dihydroxy 17a ethylethinyl 19 nor 4 androsten 3 one, 6, fluoro- 115,175 dihydroxy 17a propylethinyl 19: nor 4- andr-osten 3 one, 6 fluoro 115,175 dihydroxy 171x isopropyl ethinyl 19 nor 4 androsten: 3- one, 6 fluoro 4 115,175 dihydroxy 17cc butylethinyl- 19 nor 4 androsten 3 one, 6 fluoro 115,175- dihydroxy 17oz isobutylethinyl 19 nor 4 androsten 3 one, and 6 fluoro 115,175 dihydroxy-17atertiary butylethinyl-l9-nor-4-androsten-3-one are produced in the same manner as in Example 1B by dissolving 6 fluoro 115,175 dihydroxy 17oz methylethiny-l- 19 nor- 4 androsten 3 one, 6 fluoro 115,175 dihydroxy 170a ethylethinyl 19 nor 4 androsten- 3-one, 6 fluoro 115,175 dihydroxy 171x propylethinyl 19 nor 4 androsten 3 one, 6 fluoroll5,175 dihydroxy 17a isopropylethinyl 19 nor- 4 androsten-3-one, 6-fluoro-115,175-dihydroxy-l7a-butylethinyl 19 nor 4 androsten 3 one, 6 fiuoro- 115,175 dihydroxy 17oz iso'butylethinyl 19 nor 4 androsten 3 -one, and 6 fluoro 115,175 dihydroxy 17oz tertiary butylethinyl 19 nor 4 androsten-3-one in the appropriate acid anhydride and heating, for example, at between 160 and 150 degrees centigrade. The crude ester is isolated and crystallized in accordance with the procedure in Example 113.

EXAMPLE 3 A. 6 fluoro 175 hydroxy 17a ethinyl-4-andr0stene- 3,11-dione To a solution of 0.425 gram of 6a-fluoro-115,175-dihydroxy-17ot-ethinyl-4-androsten-3-one in twenty milliliters of glacial acetic acid there is added a solution of 0.25 gram of chromic anhydride, "one milliliter of water, and twenty milliliters of acetic acid. The reaction mixture after being allowed to stand at approximately 25 degrees centigrade for several hours is diluted with five milliliters of methanol and distilled almost to dryness at reduced pressure and the residue thus obtained is then treated with twenty milliliters of water. The product is recovered-by filtration, washed with water, dried and recrystallized from methanol and then acetonehexane to give 60: fluoro 175 hydroxy 17a ethinyl 4 androstene 3,11 dione, a crystalline solid. In like manner "65 fluoro 175 hydroxy 17a ethinyl 4 androstene 3,11 dione is obtained by the oxidation of 10 65 fluoro 115,175 dihydroxy 17 ethinyl 4-androsten-3-one. v

Similarly, 6 fluoro 175 hydroxy 17 methylethinyl 4 androstene 3,11 dione, 6 fluoro 175- hydroxy 17cc ethyl -,ethinyl 4 androstene 3,11- dione, 6 fluoro 175 hydroxy 17a propylethinyl-4- androstene 3,11 dione, 6 fluoro 175 hYdIOXY-17aisopropylethinyl 4 androstene 3,11 dione, 6-fluoro- 175 hydroxy 17a butylethinyl 4 androstene 3,11- dione, 6 fluoro 175 hydroxy 17a isobutylethinyl- 4-androstene 3,11 dione, and 6 fluoro 175 hydroxy- 170C tertiary butylethinyl 4 androstene 3,11 dione are obtained in the same manner as in Example 3A by the oxidation of the corresponding starting steroid.

B. 6 fluoro 175 hydroxy 17a 5 ethinyl-4-androstene- 3,11-dione l 7-pr0pi0nate A solution containing one gram of 6a-fluoro-175-hydroxy 17a ethinyl 4 androstene 3,11 dione in nine milliliters of propionic anhydride is heated under reflux until the reaction is substantially complete, usually for several hours. The propionic anhydride is then removed by evaporation and the residue is crystallized from aqueous methanol to give 60: fluoro 175 hydroxy-17aethinyl 4 androstene 3,11 dione l7-propionate. Treating 65 fluoro '175 hydroxy 17cc ethinyl 4- andr0stene-3,1l-dione with propionic anhydride as above is productive of 65 fluoro 175 hydroxy 17a-ethinyl- 4-androstene-3,ll-dione l7-propionate.

In the same manner shown above other 17-acylates of 6 fluoro 175 hydroxy 17oz ethinyl 4 androstene- 3,11 dione, for example, 6 fluoro 175 hydroxy-17aethinyl 4 androstene 3,11 dione 17 cyclopentylpropionate, 6 fluoro 175 hydroxy 17a ethinyl 4- androstene 3,11 dione 17 acetate, 6 fluoro 175- hydroxy 17a ethinyl 4 androstene 3,11 dione 17 butyrate, 6 fluoro 175 hydroxy 17oz ethinyl 4- androstene 3,11 dione 17 valerate, 6 fluoro 175- hydroxy 17a ethinyl 4 androstene 3,11 dione l7 hexanoate, 6 fluoro 175 hydroxy 17oz ethinyl- 4 androstene 3,11 dione l7 laurate, 6 fluoro 175- hydroxy 17a ethinyl 4 androstene 3,11 dione 17- trimethylacetate, 6 fluoro 175 hydroxy 17a ethinyl- 4 androstene 3,11 dione 17 isobutyrate, 6 fluoro- 175 hydroxy 17a ethinyl 4 androstene 3,11-dione 17 isovalerate, 6 fluoro 175 a hydroxy 17a-ethinyl- 4 androstene 3,11 dione 17-cyclohex'ane-carboxylate, 6 fluoro 175 hydroxy 17a ethinyl 4 androstene- 3,11 dione 17 benzoate, 6 fluoro 175 hydroxy-17aethinyl 4 androstene 3,11 dione 17-phenylacetate, 6 fluoro 175 hydroxy 17a ethinyl 4 androstene- 3,11 dione l7 (5-phenylpropionate), 6 fluoro 175- hydroxy 17a ethinyl 4 androstene 3,11 dione 17- (0-, m, p-toluate), 6 fluoro 175 hydroxy 17aethinyl 4 androstene 3,11 dione 17 hemisuccin'ate, 6 fluoro 175 hydroxy 17a ethinyl 4 androstene- 3,11-dione 17 hemiadipate, 6 fluoro 175 hydroxy- 17a ethinyl 4 androstene 3,11 dione 17-acrylate, 6 'fluoro 175 hydroxy 17a. ethinyl 4 androstene- 3,11 dione 17 crotonate, 6 fluoro 175 hydroxy- 17u ethinyl 4 androstene-3,11-dione 17-undecylenate, 6 fluoro 175 hydroxy 17d ethinyl 4 androstene- 3,11 dione 17 propiolate, 6 fluoro 175 hydroxy- 17=a ethinyl 4 androstene 3,11 dione 17-cinnamate, 6 fluoro 175 hydroxy 170 ethinyl 4 androstene- 3,11 dione 17 maleate, and 6 fluoro- 175 hydroxy- 170a ethinyl 4 androstene 3,11-dione 17-citraconate, are prepared by dissolving 6 fluoro 175 hydroxy-17aethinyl-4-androstene-3,l l-dione in the appropriate acid anhydride and heating, for example, at between and degrees Centigrade. accordance with the procedure above andrecrystallized to give the 6 fluoro- -hydroxy-17a-ethinyl-4-androstene-3,11-dione 17-acylate.' If the corresponding acid anhydride is solid, an inert solvent such as toluene,

The crude ester is isolated in 1 1 xylene, or dioxane can be added to effect solution and to provide a liquid esterification medium.

The 17 propionates of 6 fluoro 175'- hydroxy-17amethylethinyl 4 androstene 3,11 dione, 6 fluoro- 175 hydroxy 17a ethylethinyl 4 androstene 3,11- dione, 6 fluoro 175 hydroxy 17oz, propylethinyl- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 17a isopropylethinyl 4 androstene 3,11 dione, 6- fluoro 175 hydroxy 171x butylethinyl 4-androstene- 3,11 dione, 6 fluoro 175 hydroxy 17a isobutylethinyl 4 androstene 3,11 dione, and 6 fluoro-175- hydroxy 17a tertiary butylethinyl 4 androstene- 3,11 dione, are obtainedin the same manner as in Example 313 by treating the corresponding steroid with propionic anhydride. Other 17-acylates of 6-fluoro-175- hydroxy 17oz methylethinyl 4 androstene-3,11-dione, 6 fluoro 175 hydroxy 17a ethylethinyl 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17apropylethinyl 4 androstene 3,11 dione, 6 fluoro- 175 hydroxy 17a isopropylethinyl 4 androstene- 3,11 dione, 6 fluoro 175 hydroxy Hot-butylethinyl- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 170; isobutylethinyl 4 androstene 3,11 dione, and 6 fluoro 175 hydroxy 17a tertiary butylethinyl- 4 androstene 3,11 dione, are produced in the same manner as in Example 313 by dissolving 6-fluoro-175- hydroxy 17a methylethinyl 4 androstene-3,1l-dione, 6 fluoro 175 hydroxy 17a ethylethinyl 4 androstene 3,11 dione, 6 fluoro 175 hydroxy-17apropylethinyl 4 androstene 3,11 dione, 6 fluoro- 175 hydroxy 17a isopropylethinyl 4 androstene- 3,l1 dione, 6 fluoro 175 hydroxy Not-butylethinyl- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 17a isobutylethinyl 4 androstene 3,11 dione, and

6 fluoro 175 hydroxy 17a tertiary butylethinyl- A. 6 fluoro 175 hydroxy 170a ethinyl 19 nor 4 androstene-3,1 1 -dine 1n the same manner shown in Example 3A, treating 6a fluoro 115,175 dihydroxy 17a ethinyl 19 nor- 4-androsten-3-one with chromic anhydride is productive of 6a fluoro 175 hydroxy 17o: ethinyl 19 nor- 4-androstene-3,11-dione. In like manner 65-fluoro-175- hydroxy 17m ethinyl 19 nor 4 androstene 3,1ldione is obtained from 65 fluoro 115,175 di hydroxy 17cc ethinyl 19 nor 4 androstene 3- one by oxidation with chromic anhydride.

Similarly, 6-fluoro-175-hydroxy-17a-methylethinyl-19- nor 4- androstene 3,11 dione, 6 fluoro 175 hydroxy 17a ethylethinyl 19 nor 4 androstene 3, ll-dione, 6-fluoro-175-hydroxy-17u-propylethinyl-19-nor- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 1711 isopropylethinyl 19 nor 4 androstene 3,11- dione, 6 fluoro 175 hydroxy 17a butylethinyl 19- nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17a isobutylethinyl 19 nor 4 androstene- 3,11-dione, and 6-fluoro-175-hydroxy-17u-tertiary butylethinyl-19-nor-4-androstene-3,1l-dione are obtained in the same manner as in Example 3A by oxidation of the corresponding starting steroid.

B. 6 fluoro 17,3 hydroxy 17 ethinyl 19 nor 4- androstene-3,1 I-dione 17-pr0pi0nate In the same manner shown in Example 3B, treating 6oz fluoro 175 hydroxy 17oz ethinyl 19 nor 4- androstene-3,11-dione with propionic anhydride is productive of 6a-fluoro-175-hydroxy-17a-ethinyl-19-nor-4- androstene-3,11-dione 17-propionate. In like manner 65- fluoro 175, hydroxy 17a ethinyl 19 nor 4 an- 12 drostene-3,11-dione 17-propionate is obtained by esterifying 65-fluoro-175-hydroxy-l7a-ethinyl-19-nor-4-androstene-3,11-dione with propionic anhydride.

Similarly other 17-acylates are prepared by dissolving 6 fluoro 175 hydroxy 17cc ethinyl 19 nor 4- androstene-3,11-dione in the appropriate acid anhydride,

heating, for example, at between and degrees centigrade and isolating the product as shown in Example 3B.

The 17-propionates of 6-fluoro-175-hydroxy-17a-meth-- ylethinyl- 19 nor 4 androstene 3,11 dione, 6 fluoro hydroxy 17a ethylethinyl 19 nor 4 androstene 3,11- dione, 6 fluoro 175 hydroxy 17ozpropylethinyl 19 nor 4 androstene 3,11 dione, 6- fiuoro 1715 hydroxy 17a isopropylethinyl 19 nor- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 17cc butylethinyl 19 nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 17a isobutylethinyl 19- nor-4-androstene-3,1l-dione, and 6-fluoro-175-hydroxy- 17a tertiarybutylethinyl 19 nor 4 androstene-3, ll-dione, are obtained in the same manner as in Example 3B by treating the corresponding steroid with propionic anhydride. Other 17-acylates of 6-fluoro-175-hydroxy- 17oz methyletbinyl 19 nor 4 androstene 3,11-dione, 6 fluoro 175 hydroxy 17oz ethylethinyl 19- nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17cc propylethinyl 19 nor 4 androstene- 3,11-dione, 6-fluoro-175-hydroxy-17a-isopropylethinyl-19- nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17oz butylethinyl 19 nor 4 androstene 3, l1 dione, 6 fluoro 175 hydroxy 17a isobutylethinyl-19-nor-4-androstene-3,11'-dione, and 6-fiu0ro-175- hydroxy 17oz tertiary butylethinyl 19 nor 4 androstene-3,11-dione are produced in the same manner as in Example 3B by dissolving 6-fluor0-175-hydroxy-17umethylethinyl 19 nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17a ethylethinyl 19 nor- 4 androstene 3,11 dione, 6 fluoro 175 hydroxy- 17cc -propylethinyl 19 nor 4 androstene 3,11 dione, 6 fluoro 175 hydroxy 17a isopropylethinyl- 19 nor 4 androstene 3,11 dione, 6 fluoro 175- hydroxy 17oz butylethinyl 19 nor 4 androstene- 3,11 dione, 6 fluoro 175 hydroxy 17a isobutylethinyl 19 nor 4 androstene 3,11 dione, and 6- fiuoro 175 hydroxy 17a tertiary butylethinyl 19- nor-4-and1'ostene-3,1l-dione in the appropriate acid anhydride and heating, for example, at between 100 and 150 degrees centigrade. The crude ester is isolated in accordance with the procedure in Example 3B.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

' 1. A compound of the formula:

O Ra o en! wherein R is selected from the group consisting of hydrogen and methyl, R is selected from the group consisting of hydrogen and an alkyl radical containing from one to four carbon atoms, inclusive, R is selected from -the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and X is selected from the group consisting of CHOH and C=O.

2. 6 fluoro 115,175 dihydroxy 17cc ethinyl- 4 androsten 3 one.

3. 6a fiuoro 115,175 dihydroxy 17a ethinyl 4- androsten 3 one.

4. 6 fluoro 115,175 dihydroxy 17a ethinyl --4- androsten 3 one 17 acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

5. 6a fiuoro 115,175 dihydroxy 17a ethinyl 4- androsten 3 one 17 acylates in which the acyl radical is that of a hydrocarbon carhoxylic acid containing from one to twelve carbon atoms, inclusive.

6. 6a fluoro 115,175 dihydroxy 17a ethinyl 4- androsten 3 one 17 propionate.

7. 6 fluoro 175 hydroxy 17a ethinyl 4- androstene 3,11 dione.

8. 6a fluoro 175 hydroxy 17a ethinyl 4- androstene 3,11 dione.

9. 6 fiuoro 175 hydroxy 17cc ethinyl 4- androstene 3,11 dione 17 acylates in which theacyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

10. 60c fiuoro 175 hydroxy 17oz ethinyl 4- androstene 3,11 dione 17 acylates in which the acyl radicals is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

11. 6a fluoro 175 hydroxy 17a ethinyl 4- androstene 3,11 dione 17 propionate.

12. 6 fluoro 115,175 dihydroxy 17a methylcthinyl 4 androsten 3 one.

13. 6a fluoro 115,175 dihydroxy 17a methylethinyl 4 androsten 3 one.

14. 6 fluoro 115,175 dihydroxy 17a methylethinyl 4 androsten 3 one 17 acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

15. 6a fiuoro 115,175 dihydroxy 17a methylethinyl 4 androsten 3 one 17 acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

16. 6a fiuoro 115,175 dihydroxy 17oz methylethinyl 4 androsten 3 one 17 propionate.

17. 6 fluoro hydroxy 17oz methylethinyl- 4 androstene 3,11 dione.

18. 6a fluoro 175 hydroxy 17oz methylethinyl- 4 androstene 3,11 dione.

19. 6 fluoro -175 hydroxy 17oz methylethinyl- 4 androstene 3,11 dione 17 acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

20. 6oz fiuoro 175 hydroxy 17a methylethinyl- 4 androstene 3,11 dione 17 acylates in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

21. 6oz fluoro 175 hydroxy 17a rnethylethinyl- 4 androstene 3,11 dione 17 propionate.

No references cited. 

1. A COMPOUND OF THE FORMULA: 